Many pharmaceutical and industrial processes rely upon crystallization to assure purity and polymorphic control of a product. Representative of such processes are selective polymorphic crystallization of progesterone and separation of hydrocarbon isomers. For such processes, the attainment of a specified level of purity is desired that does not vary between batches or over time in a continuous production mode. While it is conventional to utilize a turbidity meter to measure the amount of light scattering associated with the progression of crystallization, this has limited applicability owing to the fact that most of the critical events controlling crystallization have already occurred by the time crystallites are of a sufficient size to scatter light. This, coupled with lack of additional sampling ports available to monitor especially in microreaction vessels, has left many crystallization reactions lacking adequate in situ monitoring.
There exists a number of analytical methods for offline sampling of crystal analysis regarding polymorphism and crystal quality. These methods include differential scanning calorimetry, x-ray diffraction, infrared spectroscopy and Raman spectroscopy. Unfortunately, offline sampling cannot provide information in a timely manner to adjust crystallization parameters to drive the process toward a desired result. Additionally, offline sampling is not necessarily indicative of material within a reaction vessel as polymorphic transformations and crystal growth may continue during sample filtration, drying and analytical sample preparation.
While both infrared absorption spectroscopy and Raman spectroscopy are potentially useful to monitor chemical and physical processes in real time, Raman spectroscopy affords certain advantages relative to infrared absorption spectroscopy including a weak Raman signal associated with water and other important crystallization solvents thereby facilitating true in situ crystallization monitoring. Additionally, Raman spectroscopy is more amenable to remote sensing via fiber optics. Thus, there exists a need for a method of monitoring sample crystallization from a solution in real time by way of Raman spectroscopy that affords at least turbidity meter information and ideally information about microcrystallites before appreciable light scattering occurs.